BACKGROUND. Mutations in the KRAS oncogene occur in approximately 30% of cancer yet little therapeutic options exist for the treatment of these cancers. Various strategies to target KRAS protein have not been successful in the past. PURPOSE. In this project we aim to take a different approach to discover inhibitors of the KRAS oncoprotein. We are using high-throughput screening of a small molecule library to identify compounds that specifically cause the degradation of the KRAS oncoprotein. SIGNIFICANT MATERIALS AND METHODS. A cell-based assay was developed to measure the effect of small molecules on KRAS protein levels in a high-throughput format. FY2013 ACCOMPLISHMENT. We have conducted the screen against 2,000 compounds in collaboration with NCATS. We have identified candidates with activity and we are currently conducting in-depth validation of these hits.